Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer

Myles C. Hodgson, Long Jiang Shao, Anna Frolov, Rile Li, Leif E. Peterson, Gustavo Ayala, Michael M. Ittmann, Nancy L. Weigel, Irina U. Agoulnik

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Patients with metastatic prostate cancer who undergo androgen-ablation therapy invariably relapse and develop incurable castration-resistant disease. Activation of the prosurvival Akt pathway accompanies androgen ablation. We discovered that the androgen receptor induces the expression of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) but not PTEN in prostate cancer cells. Optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR. INPP4B dephosphorylates phosphatidylinositol-3, 4-bisphosphate, which leads to reduced phosphorylation and activity of Akt. In support of a key role for INPP4B in Akt control, INPP4B depletion activated Akt and increased cellular proliferation. The clinical significance of INPP4B in androgen-dependent prostate cancers was determined in normal or primary tumor prostate tissues derived from radical prostatectomy specimens. In primary tumors, the expression of both INPP4B and PTEN was substantially reduced compared with normal tissue. Further, the decreased expression of INPP4B reduced the time to biochemical recurrence. Thus, androgen ablation can activate the Akt pathway via INPP4B downregulation, thereby mitigating the antitumor effects of androgen ablation. Our findings reinforce the concept that patients undergoing androgen ablation may benefit from Akttargeting therapies.

Original languageEnglish (US)
Pages (from-to)572-582
Number of pages11
JournalCancer research
Volume71
Issue number2
DOIs
StatePublished - Jan 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer'. Together they form a unique fingerprint.

Cite this